The HLA region on the sixth chromosome influences the development of rheumatoid arthritis (RA) and drug toxicity related to its treatment. HLA DR4 is associated with the development of the disease and HLA DR3 with toxicity to gold and penicillamine. It is not known if it is HLA DR genes that are directly involved in the disease process or if it is genes that are closely linked to them. If closely linked genes are implicated in the disease, it is unlikely that all HLA DR4 and all HLA DR3 bearing chromosomes carry the disease related gene. As a consequence HLA DR4 HLA DR3 bearing chromosomes will not predispose equally to disease. To test the hypothesis that there is selectivity among HLA DR4 and HLA amd DR3 bearing chromosomes in their capacity to predispose it is necessary to examine genotypes. Phenotypes of the disease proband will not suffice, family studies being required to identify the genotypes. The HLA genotypes (or haplo-types) which will be established in the proposed studies consist of alleles of 10-12 closely linked loci. Studies of such extended haplotypes in other HLA associated diseases including Juvenile Diabetes mellitus have been used to show some chromosomes have an increased risk for disease compared with others having the same HLA DR allele. Specific Aims: 1) Mapping genes associated with RA and related drug toxicity. Family studies will be used to establish haplotypes thereby defining groups of linked genes predisposing to disease. 2) Investigation into the penetrance of the HLA region haplotypes defined in l. above, for the development of disease. 3) A prospective study of HLA typing in identifying those at risk for drug toxicity in the treatment of RA. Methodology: The genes to be tested are those of the HLA region, including the closely linked complement and glyoxalase polymorphisms. Long-term objectives: The identification of the genes predisposing to RA will define the inherited predisposition to the disease. As knowledge of the immunogenetics of RA improves new therapeutic stratagems can be devised on a rational basis the eventual goal being a reduction in the morbidity from this chronic disabling disease. An important preliminary step will be to limit the considerable toxicity associated with the presently available drugs. It is believed HLA typing will contribute to a reduction in these toxic effects by allowing the physician to avoid particular drugs in the genetically susceptible individual.